GST alleles and oxidant pollutants in the pathogenesis of asthma. It is generally acknowledged that the etiology of many lung diseases involves a complex interplay between the genetics of the individual and his or her exposure to multiple environmental stimuli. Inhaled pollutants can contribute to the risk for development of lung disease through a number of pathologic processes, including inflammation of the airways. It is therefore reasonable to believe that individual differences in the activity of genes which function to detoxify and thus limit exposure to noxious agents can impact, not only the risk for disease, but also pathogenesis of disease and particularly the severity of the disease in affected individuals. Glutathione S-transferases (GSTs) are a superfamily of enzymes responsible for the detoxification of a wide range of xenobiotics and also for the response of cells to oxidative stress. The polymorphic nature of this family of genes and their expression in epithelial cells of lung and gut, cells continually exposed to environmental agents, has made them the focus of numerous human genetic studies. Many of these studies support a role for polymorphism in this gene family in determination of risk of developing asthma, COPD, chronic bronchitis and occupational lung disease. Here we test the hypothesis that the combination of GST alleles expressed by an individual determines his/her response to oxidant pollutant exposures and that this contributes to his or her risk for development of severe lung disease. PUBLIC HEALTH RELEVANCE: Genetic studies are identifying an ever increasing number of polymorphisms and environmental factors linked to risk for development of lung diseases. Determining the functionality of these genetic variations has proved difficult, particularly when no change in the primary structure of the encoded protein is predicted by the polymorphism. Furthermore, understanding which genetic variants are essential when combined with environmental risk factors to affect the development of lung diseases remains a largely unanswered question. In this application, we present the development of a new strategy for the exchange of mouse genes with their human orthologues. We show that after this exchange SNPs can be introduced into the human DNA segment of the mouse genome. As this genetic manipulation is carried out in mouse embryonic stem cells, it is possible to generate mouse lines that differ only in a particular polymorphism associated with risk for disease in the human population. These mice can be used to study the impact of this polymorphism on gene expression, protein function, and development, as well as whether combinations of genetic variants may act additively in development of lung disease or whether additional exposure to environmental risk factors are necessary for disease development.